Mental stress causes constriction of atherosclerotic coronary arteries. Because this response may be mediated by sympathetic activation, we assessed the impact of `-adrenergic blockade with phentolamine on coronary vasomotion and on cardiac and total body norepinephrine. Eleven patients with coronary artery disease underwent measurements of left anterior descending coronary artery diameter, left anterior descending artery flow (derived from Doppler flow velocity measurements), and norepinepherine spillover, at rest and during 10 minutes of mental stress induced by a stressful video game. Patients were then randomized to receive either intracoronary phentolamine to achieve `-adrenergic blockade, or saline before repeating the mental stress. With phentolamine, basal cardiac norepinepherine spillover increased, whereas total body epinephrine spillover was unchanged, indicating a local cardiac effect. Systemic hemodynamic changes were similar during both periods of mental stress. We found that `-adrenergic blockade with phentolamine prevented constriction of atherosclerotic coronary lesions and reduced coronary resistance during mental stress, despite an increased cardiac norepinepherine spillover. Those patients who received saline during their repeat mental stress had similar vasomotor and norepinepherine spillover changes as during their initial mental stress study. Thus, we conclude that alpha-adrenergic blockade prevents the deleterious vasomotor responses of atherosclerotic coronary arteries during mental stress.